CN110746471B - Preparation method of fondaparinux sodium disaccharide intermediate - Google Patents
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Abstract
The invention discloses a preparation method of fondaparinux sodium disaccharide intermediate, which is characterized in that 1-O-substituent sulfonyl-2, 3-di-O-benzyl-4, 6-O-benzylidene-beta-D-glucopyranose reacts with 1, 6-dehydration-2-deoxy-2-azido-3-O-acetyl-beta-D-glucopyranose to directly prepare the fondaparinux sodium disaccharide intermediate shown in formula I; meanwhile, the fondaparinux sodium disaccharide intermediate shown in the formula I is used as a raw material to synthesize the fondaparinux sodium disaccharide intermediate shown in the formula IV; the method has the advantages of simplicity, few steps, high yield, high atom utilization rate and few three wastes, and is suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the field of chemical synthesis of sugar, and particularly relates to a preparation method of a fondaparinux sodium disaccharide intermediate.
Background
Fondaparinux sodium (Fondaparinux sodium) is an artificially synthesized heparin pentasaccharide drug and is the first indirect inhibitor of antithrombin dependent factor Xa developed by Sanofi Winthrop industries, france. The chemical structure is shown as the following formula (D, E, F, G, H represents 5 monosaccharide segments from left to right, respectively).
The total synthetic route of fondaparinux sodium is long, and the reaction steps are from 50 steps to over 70 steps. The main construction strategies at present are two (D + EF) + GH and D + (EF + GH), wherein the following structure (formula IV) is an important intermediate for introducing an EF disaccharide fragment:
the intermediate of the formula IV serving as the EF disaccharide fragment is butted with the D monosaccharide fragment to form an intermediate of a D + EF trisaccharide fragment, then the intermediate is butted with an intermediate of a GH disaccharide fragment to construct an intermediate of (D + EF) + GH pentasaccharide, and finally the fondaparinux sodium is prepared through a series of reactions such as deprotection and sulfonation and the like, and the specific process steps are referred to in ChemMedChem, 2014, vol.9, pp.1071-1080.
There are several prior art methods for the preparation of disaccharide intermediate fragments (formula IV):
the method comprises the following steps: patent WO2012047174a1 discloses a process for the preparation of a disaccharide fragment (formula IV) by a multi-step reaction starting from compounds (formula V) and (formula VI) as follows:
the second method comprises the following steps: patent WO2013115817a1 discloses a preparation method of a disaccharide fragment-type benzyl carboxylate analogue of formula IV by a multi-step reaction using a disaccharide fragment compound (formula VII) as a starting material, as shown below:
the third method comprises the following steps: the method reported in the document chemdechem, 2014, vol.9, pp.1071-1080 uses beta-D-glucose pentaacetate as a raw material to prepare a monosaccharide intermediate (formula VIII), then the monosaccharide intermediate is butted with 1, 6-dehydration-2-deoxy-2-azido-3-O-acetyl-beta-D-glucopyranose, and finally deprotection is carried out to prepare the fondaparinux disodium disaccharide intermediate (formula IV):
for another example, chinese patent CN105622678A discloses a method for preparing cellobiose as a starting material, which also adopts a multi-step reaction (about 10 steps) to prepare fondaparinux sodium disaccharide intermediate (formula IV), and the cellobiose raw material is expensive;
however, all the prior art routes and solutions described above have some problems as follows: the preparation method has the advantages that the route is long, the process is complicated, the side reactions generated in the whole preparation process are more due to more steps, various complex impurities are generated and further brought to intermediates and products in the next steps, so that the quality and the yield of the products are reduced, and the amplification production is not facilitated.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the prior art and provide a novel preparation method for preparing the fondaparinux sodium disaccharide intermediate, which can obtain more ideal product yield, has high atom utilization rate and less three wastes and is suitable for industrial large-scale production.
In order to solve the technical problems, the invention adopts a technical scheme as follows: a preparation method of fondaparinux sodium disaccharide intermediate shown as a formula I comprises the following steps: reacting a compound represented by formula I-1 (Chinese name: 1-O-substituent sulfonyl-2, 3-bis-O-benzyl-4, 6-O-benzylidene- β -D-glucopyranose) with a compound represented by formula I-2 (Chinese name: 1, 6-anhydro-2-deoxy-2-azido-3-O-acetyl- β -D-glucopyranose) to produce the compound represented by formula I:
in the formula I-1, X is methyl, trifluoromethyl or p-methylphenyl; wherein the reaction is controlled to be carried out at a temperature of-60 ℃ to 60 ℃ in the presence of an organic base in an organic solvent.
According to some preferred aspects of the present invention, the compound of formula I-1 and the compound of formula I-2 are fed in a molar ratio of 1: 1.1 to 1.3.
According to some preferred aspects of the invention, the organic base is a combination of one or more selected from the group consisting of 2,4, 6-trimethylpyridine, 2,4, 6-trimethylpyrimidine, triethylamine, tributylamine, 2,4, 6-tri-tert-butylpyridine and 2,4, 6-tri-tert-butylpyrimidine. Compared with other alkali, the organic alkali is more beneficial to the selectivity of target products, and has higher yield and better purity.
According to some preferred aspects of the present invention, the compound of formula I-1 and the organic base are fed in a molar ratio of 1: 1.1 to 3, preferably 1: 1.5 to 2.5.
According to some specific and preferred aspects of the present invention, the reaction is controlled to be carried out at a temperature of-50 ℃ to 30 ℃ for a reaction time of 1 to 12 hours.
According to some specific and preferred aspects of the present invention, the organic solvent is a combination of one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, methanol, ethanol, isopropanol, N-propanol, tert-butanol, N-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, N-methylpyrrolidone, toluene, dichloromethane, dichloroethane, chloroform and 1, 4-dioxane.
According to some embodiments of the invention, the organic solvent is a combination of one or more selected from the group consisting of N, N-dimethylformamide, isopropanol, and tetrahydrofuran.
According to some specific and preferred aspects of the present invention, the compound represented by formula I-1 is prepared by the following method: reacting a compound of formula e with XSO2Cl (X is methyl, trifluoromethyl or p-methylphenyl) reacts in dichloromethane under the action of triethylamine to generate a compound shown as a formula I-1;
according to some specific and preferred aspects of the present invention, the compound of formula e is prepared by: reacting the compound shown in the formula d with water in dimethyl sulfoxide under the action of potassium tert-butoxide to generate a compound shown in a formula e;
according to some specific and preferred aspects of the present invention, the compound represented by formula d is prepared by the following method: reacting the compound shown in the formula c with benzyl bromide in N, N-Dimethylformamide (DMF) under the action of sodium hydrogen (NaH) to generate a compound shown in a formula d;
according to some specific and preferred aspects of the present invention, the compound represented by formula c is prepared by the following method: reacting the compound shown in the formula b with benzaldehyde dimethyl acetal in tetrahydrofuran under the action of p-toluenesulfonic acid to generate a compound shown in a formula c;
according to some specific and preferred aspects of the present invention, the compound represented by formula b is prepared by the following method: reacting the compound shown in the formula a with allyl alcohol in water under the action of immobilized beta-glucosidase to generate a compound shown in a formula b;
the invention provides another technical scheme that: a preparation method of fondaparinux sodium disaccharide intermediate shown in formula IV comprises the step of preparing the compound shown in formula IV from the compound shown in formula I,
the preparation method also comprises the step of preparing the fondaparinux sodium disaccharide intermediate shown in the formula I.
According to some specific aspects of the present invention, in the preparation method of the fondaparinux sodium disaccharide intermediate represented by formula IV, the step of preparing the compound represented by formula IV from the compound represented by formula I specifically includes:
(1) carrying out debenzylation reaction on the intermediate (the compound shown in the formula I) in an acid solution to obtain the intermediate (the compound shown in the formula II), wherein the reaction formula is as follows:
(2) carrying out oxidation reaction on the intermediate (the compound shown in the formula II) to obtain the intermediate (the compound shown in the formula III), wherein the reaction formula is as follows:
(3) the intermediate (the compound shown in the formula III) is subjected to esterification reaction to obtain a fondaparinux sodium disaccharide intermediate (the compound shown in the formula IV), and the reaction formula is as follows:
due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention creatively uses 1-O-substituent sulfonyl-2, 3-bi-O-benzyl-4, 6-O-benzylidene-beta-D-glucopyranose (a compound shown as a formula I-1) as an initial raw material to be matched with 1, 6-dehydration-2-deoxidation-2-azido-3-O-acetyl-beta-D-glucopyranose for reaction to directly generate the fondaparinux disodium disaccharide intermediate shown as the formula I, not only has high yield, and because the steps are less, the process operation is simpler, the side reaction is reduced in each step, the impurities are less, the process is controllable, no pollutant is generated, meanwhile, the starting raw materials are cheap and easy to obtain, the atom utilization rate is high, the cost is lower, and the industrial scale-up production of fondaparinux sodium is facilitated.
Detailed Description
The above-described scheme is further illustrated below with reference to specific examples; it is to be understood that these embodiments are provided to illustrate the general principles, essential features and advantages of the present invention, and the present invention is not limited in scope by the following embodiments; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
In the following, all starting materials are either commercially available or prepared by conventional methods in the art, unless otherwise specified.
The following examples 1-3 prepare compounds of formula I-1 as follows:
EXAMPLE 1 preparation of Compound represented by formula I-1 (X is methyl)
Example 1-1:preparation of a Compound of formula b: the method specifically comprises the following steps:
d-glucose (180g, 1.0mol), water (300ml), allyl alcohol (1500g, 25.8mol) and immobilized beta-D-glucosidase (150g, 3000u) are mixed and placed in a shaking table, and the temperature is controlled to be 50 ℃ for reaction for 72 hours. Filtering, washing the filter cake with a small amount of water and ethyl acetate to obtain the immobilized enzyme which can be recycled. Recovering allyl alcohol from the filtrate under reduced pressure, purifying the residual liquid by a rapid silica gel column, collecting the positive component, concentrating and drying to obtain an intermediate (the compound shown in the formula b), wherein the intermediate is a white solid (156g), the yield is 71%, and the purity is 97.8%.
Examples 1 to 2:preparation of a Compound of formula c:
the intermediate (compound represented by formula b) (110g, 0.50mol) was dissolved in tetrahydrofuran (500mL), p-toluenesulfonic acid monohydrate (5g, 0.026mol) and benzaldehyde dimethyl acetal (225g, 1.48mol) were added, and the reaction was stirred at 42. + -. 1 ℃ for 4 hours. Cooling to 23 + -1 deg.C, adding saturated sodium bicarbonate solution to adjust pH to 7-8, concentrating under reduced pressure to dryness, and purifying the residual liquid with rapid column to obtain intermediate (compound shown in formula c) as light yellow solid (125g), with yield of 81% and purity of 98.6%.
Examples 1 to 3:of compounds of formula dPreparation:
the intermediate (compound of formula c) (120g, 0.39mol) was dissolved in anhydrous DMF (1000ml) under nitrogen and cooled to 0 ℃. NaH (60%, 34g, 0.85mol) was added thereto, and the mixture was stirred at 3. + -. 1 ℃ for 2 hours. Benzyl bromide (140g, 0.82mol) is added dropwise at the temperature of 3 +/-1 ℃, and the temperature is raised to 23 +/-1 ℃ after the addition is finished, and the reaction is stirred for 3 hours. The reaction was quenched with methanol (2ml) and concentrated under reduced pressure. The residue was diluted with water (1000ml), extracted with dichloromethane (1000ml), the organic phase was washed with water, washed with saturated brine, and concentrated to dryness under reduced pressure to give an intermediate (compound represented by formula d) as a yellow oil (171g), yield 90%, purity 95.1%.
Examples 1 to 4:preparation of a Compound of formula e:
the intermediate (compound represented by formula d) (147g, 0.3mol) was dissolved in DMSO (1500ml), potassium tert-butoxide (75g, 0.67mol) was added thereto while controlling the temperature at 0 to 5 ℃ and water (5ml) was added dropwise. The temperature is increased to 55 plus or minus 1 ℃, the mixture is stirred and reacted for 1 hour, the mixture is cooled to 23 plus or minus 1 ℃, and the reaction solution is poured into 500ml of saturated sodium bicarbonate. Elemental iodine (190g, 0.75mol) was added and the reaction was continued with stirring for 1 hour. Solid sodium bisulfite (104g, 1mol) was added at 23. + -. 1 ℃ and stirring was continued for 1 hour. The reaction mixture was extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by flash silica gel column to give an intermediate (compound represented by formula e) as a yellow oil (109g), yield 81%, purity 97.2%.
Examples 1 to 5:preparation of a Compound represented by the formula I-1 (X is methyl):
the intermediate (the compound shown in the formula e) (22.4g, 0.05mol) is dissolved in dichloromethane (100ml), triethylamine (10g, 0.1mol) is added, methanesulfonyl chloride (9.2g, 0.08mol) is added dropwise at-18 +/-1 ℃ under the protection of nitrogen, and the dropwise addition is stirred and reacted for 2 hours. Methanol (2ml) is added at the temperature of minus 18 plus or minus 1 ℃, the temperature is raised to 23 plus or minus 1 ℃, and the mixture is stirred for 1 hour. The reaction solution was purified by flash silica gel column to obtain a compound represented by the formula I-1 (X is methyl) as a white solid (24.4g), in 93% yield and 97.1% purity.
Example 2 preparation of Compound represented by formula I-1 (X is trifluoromethyl)
The compound of formula e was prepared as in examples 1-1 to 1-4 of example 1.
Preparation of a Compound represented by formula I-1: the method specifically comprises the following steps:
the intermediate (the compound shown in the formula e) (22.4g, 0.05mol) is dissolved in dichloromethane (100ml), triethylamine (10g, 0.1mol) is added, trifluoromethanesulfonyl chloride (13.6g, 0.08mol) is added dropwise at-18 +/-1 ℃ under the protection of nitrogen, and the reaction is stirred for 2 hours after the dropwise addition. Methanol (2ml) is added at the temperature of minus 18 plus or minus 1 ℃, the temperature is raised to 23 plus or minus 1 ℃, and the mixture is stirred for 1 hour. The reaction solution was purified by a flash silica gel column to obtain a compound represented by the formula I-1 (X is trifluoromethyl) as a white solid (26.0g), in a yield of 90% and in a purity of 97.4%.
Example 3 preparation of Compound represented by formula I-1 (X is p-methylphenyl)
The compound of formula e was prepared as in examples 1-1 to 1-4 of example 1.
Preparation of a Compound represented by formula I-1: the method specifically comprises the following steps:
dissolving the intermediate (the compound shown in the formula e) (22.4g, 0.05mol) in dichloromethane (100ml), adding triethylamine (10g, 0.1mol), dropwise adding p-toluenesulfonyl chloride (15.2g, 0.08mol) at-18 +/-1 ℃ under the protection of nitrogen, and stirring for reacting for 2 hours after dropwise adding. Methanol (2ml) is added at the temperature of minus 18 plus or minus 1 ℃, the temperature is raised to 23 plus or minus 1 ℃, and the mixture is stirred for 1 hour. The reaction solution was purified by means of a flash silica gel column to obtain a compound represented by the formula I-1 (X is p-methylphenyl) as a white solid (27.4g), yield 91% and purity 97.3%.
The following examples 4-6 prepare fondaparinux sodium disaccharide intermediates of formula IV as follows:
example 4 preparation of fondaparinux sodium disaccharide intermediates of formula IV
Example 4-1:preparation of the Compound of formula I
Dissolving 1-O-methylsulfonyl-2, 3-bis-O-benzyl-4, 6-O-benzylidene-beta-D-glucopyranose (25.0g,47.5mmol, the compound shown in the formula I-1, X is methyl) in dichloromethane (550mL), controlling the temperature to be 20 ℃ below zero, adding 2,4, 6-tri-tert-butylpyrimidine (23.6g, 93mmol), 1, 6-dehydration-2-deoxidation-2-azido-3-O-acetyl-beta-D-glucopyranose (12.0g,52.4mol, the compound shown in the formula I-2), controlling the temperature to be 20 ℃ below zero, stirring for reaction for 2 hours, washing with water after the reaction is finished, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing a crude product by using an ethyl acetate-petroleum ether mixed solvent, the intermediate (compound of formula I) was obtained as a white solid (29.9g) in 95.4% yield and 98.5% purity.
Example 4-2:preparation of the Compound of formula II
Mixing the intermediate (the compound shown in the formula I) (29.9g,45.3mmol) with 80% acetic acid solution (300mL), stirring and reacting at 60 ℃ for 7h, after the reaction is finished, carrying out reduced pressure rotary evaporation to dryness, extracting dichloromethane, washing with 10% sodium bicarbonate solution and salt water in sequence, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and recrystallizing the crude product with ethyl acetate-petroleum ether mixed solvent to obtain the intermediate (the compound shown in the formula II), wherein the white solid (24.6g) is obtained, the yield is 95.0%, and the purity is 98.2%.
Examples 4 to 3:preparation of the Compound of formula III
Adding an intermediate (a compound shown in a formula II) (24.6g,43.0mmol) into a mixed solution of dichloromethane (250mL) and water (130mL), adding 2,2,6, 6-tetramethylpiperidine oxide (1.3g,8.3mmol) and iodobenzene diacetic acid (41.6g,129.2mmol), stirring the reaction mixture at 30 ℃ for 1h, after the reaction is finished, slowly dropwise adding a 10% sodium thiosulfate solution under ice bath cooling, stirring for 10min, carrying out layering, extracting an aqueous phase with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and carrying out reduced pressure rotary evaporation to dryness to obtain a crude intermediate (a compound shown in a formula III) which is directly fed into the next reaction.
Examples 4 to 4:preparation of fondaparinux sodium disaccharide intermediate (Compound shown in formula IV)
Dissolving the crude intermediate (the compound shown in the formula III) obtained in the previous step in DMF (250mL, N, N-dimethylformamide), adding potassium carbonate (3.9g,28.2mmol), slowly adding methyl iodide (15.3g,107.8mmol) while stirring, stirring at 30 ℃ for reaction for 16h, after the reaction is finished, extracting the reaction mixture by using ethyl acetate, washing by using salt water, drying by using anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, purifying the crude product by using a chromatographic column, and recrystallizing by using an ethyl acetate-petroleum ether mixed solvent to obtain the fondaparinux disodium disaccharide intermediate (the compound shown in the formula IV), wherein the intermediate is a white solid (22.6g), the yield is 87.7%, and the purity is 98.9%.
Example 5 preparation of fondaparinux sodium disaccharide intermediates of formula IV
Example 5-1:preparation of the Compound of formula I
1-O-trifluoromethanesulfonyl-2, 3-bis-O-benzyl-4, 6-O-benzylidene-beta-D-glucopyranose (18.0g,31.0mmol, the compound represented by formula I-1, X is trifluoromethyl) is dissolved in tetrahydrofuran (450mL), 2,4, 6-trimethylpyridine (7.4g, 62mmol), (1, 6-anhydro-2-deoxy-2-azido-3-O-acetyl-beta-D-glucopyranose (8.5g,37.1mol, the compound represented by formula I-2) is added at the temperature of-30 ℃, the mixture is stirred and reacted for 4 hours at the temperature of-30 ℃, after the reaction is finished, the mixture is decompressed and steamed to dryness, dichloromethane is extracted, the common salt is washed by water, the anhydrous sodium sulfate is dried, the decompressed and steamed to dryness, the crude product was recrystallized from a mixed solvent of ethyl acetate and petroleum ether to give an intermediate (compound of formula I) as a white solid (19.1g), in 93.4% yield and 98.3% purity.
Example 5-2:preparation of the Compound of formula II
Mixing the intermediate (the compound shown in the formula I) (19.1g,29.0mmol) with 80% trifluoroacetic acid solution (220mL), stirring and reacting at 35 ℃ for 6h, carrying out reduced pressure rotary evaporation to dryness after the reaction is finished, extracting dichloromethane, washing with 10% sodium bicarbonate solution and salt water in sequence, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and recrystallizing the crude product with an ethyl acetate-petroleum ether mixed solvent to obtain the intermediate (the compound shown in the formula II), wherein the white solid (16.1g) is obtained, the yield is 97.1%, and the purity is 98.0%.
Examples 5 to 3:preparation of the Compound of formula III
Adding an intermediate (a compound shown in a formula II) (16.1g,28.2mmol) into a mixed solution of dichloromethane (170mL) and water (85mL), adding 2,2,6, 6-tetramethylpiperidine oxide (0.9g,5.8mmol) and iodobenzene diacetic acid (27.2g,84.4mmol), stirring the reaction mixture at 30 ℃ for 1h, after the reaction is finished, slowly dropwise adding a 10% sodium thiosulfate solution under ice bath cooling, stirring for 10min, carrying out layering, extracting an aqueous phase with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and carrying out reduced pressure rotary evaporation to dryness to obtain a crude intermediate (a compound shown in a formula III) which is directly fed into the next reaction.
Examples 5 to 4:preparation of fondaparinux sodium disaccharide intermediate (Compound shown in formula IV)
Dissolving the crude intermediate (the compound shown in the formula III) obtained in the previous step in DMF (170mL, N, N-dimethylformamide), adding potassium carbonate (2.5g,18.1mmol), slowly adding methyl iodide (10.0g,70.5mmol) while stirring, stirring at 30 ℃ for reaction for 16h, after the reaction is finished, extracting the reaction mixture with ethyl acetate, washing with salt water, drying with anhydrous sodium sulfate, decompressing and rotary-steaming to dryness, purifying the crude product by a chromatographic column, and recrystallizing the crude product with an ethyl acetate-petroleum ether mixed solvent to obtain the fondaparinux disodium disaccharide intermediate (the compound shown in the formula IV), wherein the intermediate is a white solid (14.8g), the yield is 87.5%, and the purity is 99.1%.
Example 6 preparation of fondaparinux sodium disaccharide intermediates of formula IV
Example 6-1:preparation of the Compound of formula I
1-O-p-toluenesulfonyl-2, 3-bis-O-benzyl-4, 6-O-benzylidene-beta-D-glucopyranose (10.0g,16.6mmol, compound of formula I-1, X is p-methylphenyl) is dissolved in tetrahydrofuran (280mL), 2,4, 6-tri-tert-butylpyrimidine (8.2g, 33.2mmol), 1, 6-anhydro-2-deoxy-2-azido-3-O-acetyl-beta-D-glucopyranose (4.9g,21.4mol, compound of formula I-2) are added at-40 ℃, stirred and reacted for 1h at-40 ℃, and the temperature is raised to 0 ℃ for further reaction for 1 h. After the reaction is finished, performing reduced pressure rotary evaporation to dryness, extracting dichloromethane, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, and recrystallizing the crude product with an ethyl acetate-petroleum ether mixed solvent to obtain an intermediate (the compound shown in the formula I) which is a white solid (10.2g), wherein the yield is 93.1% and the purity is 97.7%.
Example 6-2:preparation of the Compound of formula II
Mixing the intermediate (the compound shown in the formula I) (10.2g,15.5mmol) with 80% trifluoroacetic acid solution (180mL), stirring and reacting at 30 ℃ for 6h, carrying out reduced pressure rotary evaporation to dryness after the reaction is finished, extracting dichloromethane, washing with 10% sodium bicarbonate solution and salt water in sequence, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and recrystallizing the crude product with an ethyl acetate-petroleum ether mixed solvent to obtain the intermediate (the compound shown in the formula II), wherein the white solid (8.7g) is obtained, the yield is 98.2%, and the purity is 98.3%.
Example 6 to 3:preparation of the Compound of formula III
Adding an intermediate (the compound shown in the formula II) (8.7g and 15.2mmol) into a mixed solution of dichloromethane (90mL) and water (45mL), adding 2,2,6, 6-tetramethylpiperidine oxide (0.5g and 3.2mmol) and iodobenzene diacetic acid (14.7g and 45.6mmol), stirring the reaction mixture at 30 ℃ for 1h, after the reaction is finished, slowly dropwise adding a 10% sodium thiosulfate solution under ice bath cooling, stirring for 10min, carrying out layering, extracting an aqueous phase with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and carrying out reduced pressure rotary evaporation to dryness to obtain a crude intermediate (the compound shown in the formula III) which is directly fed into the next reaction.
Examples 6 to 4:preparation of fondaparinux sodium disaccharide intermediate (Compound shown in formula IV)
Dissolving the crude intermediate (the compound shown in the formula III) obtained in the previous step in DMF (90mL, N, N-dimethylformamide), adding potassium carbonate (1.4g,10.1mmol), slowly adding methyl iodide (5.4g,38.0mol) while stirring, stirring at 30 ℃ for reaction for 16h, after the reaction is finished, extracting the reaction mixture by using ethyl acetate, washing by using salt water, drying by using anhydrous sodium sulfate, decompressing and carrying out rotary evaporation to dryness, purifying the crude product by using a chromatographic column, and recrystallizing by using an ethyl acetate-petroleum ether mixed solvent to obtain the fondaparinux disodium disaccharide intermediate (the compound shown in the formula IV), wherein the intermediate is a white solid (8.0g), the yield is 87.8%, and the purity is 99.2%.
Comparative example 1
Essentially the same as example 4, except that the process for preparing the compound of formula I is different, the procedure for preparing the compound of formula I in this example is as follows:
1.1: 1-bromo-2, 3-bis-O-benzyl-4, 6-O-benzylidene-beta-D-glucopyranose (8.5g,16.6mmol) is dissolved in dichloromethane (280mL), 2,4, 6-tri-tert-butylpyrimidine (8.2g, 33.2mmol), 1, 6-anhydro-2-deoxy-2-azido-3-O-acetyl-beta-D-glucopyranose (4.9g,21.4mol) are added with controlled temperature of 20 ℃, and the mixture is stirred at 20 ℃ for 12 hours without product generation.
1.2: bromo-2, 3-bis-O-benzyl-4, 6-O-benzylidene- β -D-glucopyranose (8.5g,16.6mmol) is dissolved in dichloromethane (280mL), 2,4, 6-tri-tert-butylpyrimidine (8.2g, 33.2mmol), 1, 6-anhydro-2-deoxy-2-azido-3-O-acetyl- β -D-glucopyranose (4.9g,21.4mol), silver triflate (8.5g, 33.2mmol) are added with temperature control at 20 ℃ and stirred for reaction for 40h at 20 ℃. After the reaction is finished, performing reduced pressure rotary evaporation to dryness, extracting dichloromethane, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, and recrystallizing the crude product with an ethyl acetate-petroleum ether mixed solvent to obtain an intermediate (the compound shown in the formula I) which is a white solid (8.9g), wherein the yield is 81% and the purity is 97.4%.
As can be seen from the above comparative examples, the reaction system requires the addition of an expensive promoter, silver triflate, and the yield is lower.
Comparative example 2
Essentially the same as example 4, except that the process for preparing the compound of formula I is different, the procedure for preparing the compound of formula I in this example is as follows:
1-S-phenyl-2, 3-bis-O-benzyl-4, 6-O-benzylidene-beta-D-glucopyranose (7.2g,16.6mmol) is dissolved in dichloromethane (280mL), 2,4, 6-tri-tert-butylpyrimidine (8.2g, 33.2mmol), 1, 6-anhydro-2-deoxy-2-azido-3-O-acetyl-beta-D-glucopyranose (4.9g,21.4mol) are added with controlled temperature at 20 ℃, and the mixture is stirred and reacted for 12 hours at 20 ℃, without producing products.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (10)
1. A preparation method of fondaparinux sodium disaccharide intermediate shown as a formula I is characterized by comprising the following steps: reacting a compound of formula I-1 with a compound of formula I-2 to produce said compound of formula I:
in the formula I-1, X is methyl, trifluoromethyl or p-methylphenyl; wherein the reaction is controlled to be carried out at a temperature of-60 ℃ to 60 ℃ in the presence of an organic base in an organic solvent; the organic base is one or more of 2,4, 6-trimethyl pyridine, 2,4, 6-trimethyl pyrimidine, triethylamine, tributylamine, 2,4, 6-tri-tert-butyl pyridine and 2,4, 6-tri-tert-butyl pyrimidine.
2. The method for preparing the fondaparinux sodium disaccharide intermediate shown in the formula I as claimed in claim 1, wherein the feeding molar ratio of the compound shown in the formula I-1 to the compound shown in the formula I-2 is 1: 1.1-1.3.
3. The method for preparing the fondaparinux sodium disaccharide intermediate shown in the formula I as claimed in claim 1, wherein the feeding molar ratio of the compound shown in the formula I-1 to the organic base is 1: 1.1-3.
4. The method for preparing fondaparinux sodium disaccharide intermediate of formula I according to claim 1, characterized in that the organic solvent is one or more selected from N, N-dimethylformamide, N-dimethylacetamide, methanol, ethanol, isopropanol, N-propanol, tert-butanol, N-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, N-methylpyrrolidone, toluene, dichloromethane, dichloroethane, chloroform and 1, 4-dioxane.
5. The preparation method of the fondaparinux sodium disaccharide intermediate shown in the formula I as claimed in claim 1, characterized in that the compound shown in the formula I-1 is prepared by the following method: reacting a compound of formula e with XSO2Cl is reacted in dichloromethane under the action of triethylamineTo generate a compound shown as a formula I-1, wherein X is methyl, trifluoromethyl or p-methylphenyl;
6. the preparation method of the fondaparinux sodium disaccharide intermediate shown in the formula I as claimed in claim 5, characterized in that the compound shown in the formula e is prepared by the following method: reacting the compound shown in the formula d with water in dimethyl sulfoxide under the action of potassium tert-butoxide to generate a compound shown in a formula e;
7. the preparation method of the fondaparinux sodium disaccharide intermediate shown in the formula I as claimed in claim 6, characterized in that the compound shown in the formula d is prepared by the following method: reacting the compound of the formula c with benzyl bromide in N, N-dimethylformamide under the action of sodium hydrogen to generate a compound shown in a formula d;
8. the preparation method of the fondaparinux sodium disaccharide intermediate shown in the formula I as claimed in claim 7, characterized in that the compound shown in the formula c is prepared by the following method: reacting the compound shown in the formula b with benzaldehyde dimethyl acetal in tetrahydrofuran under the action of p-toluenesulfonic acid to generate a compound shown in a formula c;
9. the method for preparing fondaparinux sodium disaccharide intermediate according to the formula I of claim 8, characterized in that the compound of the formula b is prepared by the following method: reacting the compound shown in the formula a with allyl alcohol in water under the action of immobilized beta-glucosidase to generate a compound shown in a formula b;
10. a preparation method of fondaparinux sodium disaccharide intermediate shown in formula IV comprises the step of preparing the compound shown in formula IV from the compound shown in formula I,
the preparation method is characterized by further comprising the step of preparing the fondaparinux sodium disaccharide intermediate shown in the formula I as claimed in any one of claims 1 to 9.
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